1. Field of the Invention
This invention relates to oncology and medicine, and more particularly to treatment of cancer. In particular, rapamycin analogs such as seco-rapamycin may be used advantageously to target the proteasome in cancer cells, optionally in conjunction with proteasome inhibitors such as bortezomib.
2. Related Art
The phenomenon of allostery, broadly defined as coupling of conformational changes between distant sites, is one of fundamental regulatory mechanisms of enzymatic catalysis (Goodey and Benkovic, 2008). Therefore, it comes to no surprise that allosteric ligands are rapidly gaining recognition as attractive drug candidates. In fact, allosteric inhibitors exhibit many benefits over the commonly utilized competitive inhibitors. They provide a much broader range of mechanisms to interfere with catalysis. They are also more specific but less likely induce drug resistance.
One of the oldest examples of a successful allosteric drug is rapamycin (sirolimus). This natural macrocyclin binds the FKBP12 (FK-binding protein 12) with its FKBP binding domain, induces dimerization of FKBP12 and mTOR (mammalian target of rapamycin) and inhibits the latter with its effector domain binding to the allosteric side adjacent to the kinase domain (FIGS. 1A-D) (Liang et al., 1999 and Banaszynski et al., 2005). The mTOR kinase regulates translation, autophagy, response to hypoxia, and glucose metabolism (Dowling et al., 2009).
Rapamycin is an established immunosuppressive drug used to prevent transplant rejection. High doses of the drug are pro-apoptotic and close synthetic analogs of rapamycin (rapalogs) are used as effective anti-cancer agents (Dowling et al., 2009). In addition, animal studies revealed surprisingly strong anti-aging effects of a prolonged treatment with low doses of rapamycin (Harrison et al., 2009).